title: Scube regulates synovial angiogenesis-related signaling.
abstract: Angiogenesis is particularly driven in the synovial microenvironment of Rheumatoid arthritis (RA), and considered as the fundamental cause for the persistent injury and chronic damage. Therefore, exploring the pathomechanism of synovial angiogenesis may provide promising prospects for vascular-targeting treatment of RA. The noval family of Scube proteins is confirmed to overlap significantly in structure characterized by epidermal growth factor (EGF)-like domains and CUB (complement subcomponents C1r/C1s, Uegf, bone morphogenetic protein-1) domain. As secreted glycoprotein and peripheral membrane protein, Scube increases its serum level in response to stimuli of inflammation and hypoxia. In rheumatoid angiogenesis-related signaling system defined by hedgehog (Hh), transforming growth factor (TGF)β and bone morphogenetic protein 2 (BMP2), Scube1 and 2 antagonize BMP2 signaling, suppressing BMP2-induced phospho-Smad1/5/8 level in vivo. Scube3 functions as an endogenous TGFβ receptor ligand, increasing Smad2/3 phosphorylation, and thus upregulates target genes involved in angiogenesis. Via obligate assistance of Scube1 and 3, Scube2 plays a center role to recruit dually lipid-modified Hh transferred from Dispatched A (DispA), increasing Hh secretion by promoting its solubility. These findings support the hypothesis that Scube may regulate synovial angiogenesis may be the ideal vascular targets for anti-rheumatic treatment of RA.
authors.affiliation: Rheumatology Center, PLA General Hospital of Chengdu Military Area Command, Chengdu, Sichuan Province, PR China; National TCM Rehab Center, PLA General Hospital of Chengdu Military Area Command, Chengdu, Sichuan Province, PR China; Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou, Guangdong Province, PR China. Electronic address: translie@live.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Mingyang
authors.initials: M
authors.lastname: Guo
authors.forename: Yonghe
authors.initials: Y
authors.lastname: Hu
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000503:physiopathology*; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013582:Synovial Fluid / Q000187:drug effects / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D002135:Calcium-Binding Proteins; D053823:Hedgehog Proteins; D008565:Membrane Proteins; C469998:SCUBE1 protein, human; C469999:SCUBE2 protein, human; C493800:SCUBE3 protein, human; D016212:Transforming Growth Factor beta